Impairing tumor vasculature (anti-angiogenesis) is important in cancer therapy. We and others have demonstrated that Stat3, which is constitutively-activated in tumor cells and required for tumor cell survival, is indispensable for production of numerous angiogenic and invasive factors, suggesting that Stat3 is a promising target for anti-angiogenesis therapy. However, the tumor stroma, which includes diverse hematopoietic cells, also produces a wide range of angiogenic and invasive factors. Therefore, effective anti-angiogenic therapy must also target tumor stromal hematopoietic cells. We recently showed that Stat3 is persistently-activated in tumor stromal hematopoietic cells, including macrophages, neutrophils and Gr1+ myeloid cells, among others. Furthermore, preliminary data indicated that tumor stromal Gr1+ myeloid cells produce angiogenic factors in a Stat3-dependent manner, suggesting that inhibiting Stat3 may block a large array of angiogenic and invasive factors produced by various tumor hematopoietic cells. Additionally, blocking Stat3 either in tumor cells or endothelial cells abrogates tumor milieu-induced angiogenesis. Prompted by these preliminary data, we hypothesize that tumor and tumor stromal cells resonate through activated Stat3, producing angiogenic and invasive factors, including those that activate Stat3 in tumor stromal cells, to promote tumor angiogenesis and thereby strengthen the survival of a tumor and its resistance to therapy. As a result, inhibiting Stat3 will target the tumor and its microenvironment, leading to efficient impairment of tumor vasculature. We have generated extensive biological systems and reagents to test this hypothesis: mouse models to induce Stat3 ablation in hematopoietic cells at various stages of tumor development;a Stat3-specific inhibitor;a long-lived form of Stat3 RNAi coupled with nanoparticles to systemically target tumor cells;and an autochthonous mouse prostate tumor model that allows Stat3 ablation in prostate when androgen surges, and in which the hematopoietic system can also be reconstituted with Stat3-null bone marrow supplementation. With these and other biological systems and reagents, the proposed studies will define whether Stat3 is an effective target for modulating tumor microenvironment and inhibiting angiogenesis.